CA2361565C - Synthesis of ethyleneimine dimer - Google Patents
Synthesis of ethyleneimine dimer Download PDFInfo
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- CA2361565C CA2361565C CA002361565A CA2361565A CA2361565C CA 2361565 C CA2361565 C CA 2361565C CA 002361565 A CA002361565 A CA 002361565A CA 2361565 A CA2361565 A CA 2361565A CA 2361565 C CA2361565 C CA 2361565C
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- ethanediamine
- ethyleneimine dimer
- haloethyl
- dihydrohalide
- yield
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method to synthesizing ethyleneimine dimer. This method of synthesis provides several advantages over previous methods: (1) the starting compounds are all relatively inexpensive, (2) the yield of product is greater than 20 % of the theoretical yield; and (3) the steps of synthesis are easy, inexpensive and amenable to large-scale production. All of these advantages allow for less expensive production of ethyleneimine dimer.
Description
SYNTHESIS OF ETHYLENEIMINE DIMER
Background of the Invention The invention relates to methods for synthesizing compounds for the selective modification of nucleic acids in biological compositions.
The transmission of viral diseases (e.g., hepatitis A, B, and C, acquired immunodeficiency syndrome, and cytomegalovirus infections) by blood or blood products is a significant problem in medicine. Other biological compositions, such as mammalian and hybridoma cell lines, products of cell lines, milk, colostrum, and sperm, can also contain infectious viruses.
Screening donor biological compositions for viral markers can help reduce the transmission of viruses to recipients, but many screening methods are directed to only a few discrete viruses, and are therefore incomplete, and may also be less than 100% sensitive. It is therefore important to inactivate viruses contained in donor blood, blood products, or other biological compositions.
A number of agents that are capable of inactivating viruses in blood have been developed. For example, ethyleneimine monomer and ethyleneimine oligomers (including dimers, trimers, and tetramers) are very effective viral inactivating agents.
Summary of the Invention In general, the invention provides a method for synthesizing ethyleneimine dimer (1-aziridineethanamine) which includes reacting 2-(2-aminoethylamino)ethanol with an aqueous HX solution, where X is a halogen, to produce N-(2-haloethyl)-1,2-ethanediamine dihvdrohalide. reacting the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide with a base in a solvent to convert the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide into ethyleneimine dimer, and then purifying the dimer from the solvent (e.g., by continuous extraction).
In preferred embodiments, the halogen is bromine (most preferred), chlorine, fluorine, or iodine. In another preferred embodiment, the HX is diluted, such that the solution is 30-55% (w/w) HX. In yet another preferred embodiment, the solvent includes a C,_6alcohol (e.g., ethanol or methanol) or water.
In other preferred embodiments, the HX is added drop-wise to the 2-(2-aminoethylamino)ethanol, the temperature of the 2-(2-aminoethylamino) ethanol is less than 10 C during the addition of the HX, and the reaction of 2-(2-aminoethyl amino)ethanol with HX includes the step of refluxing. Preferably, the yield of the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide from this reaction is at least 50% of the theoretical yield.
More preferably, the yield is at least 75% of the theoretical yield.
In still other preferred embodiments, reacting the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide to produce ethyleneimine dimer includes the steps of refluxing and distillation. Preferably, the yield of ethyleneimine dimer from this reaction is at least 20% of the theoretical yield. More preferably, the yield is at least 25% of the theoretical yield, and most preferably, the yield is at least 30% of the theoretical yield.
Preferably, the ethyleneimine dimer which results from the method of synthesis is at least 90% pure, more preferably at least 95% pure, and most preferably at least 98% pure.
The method of synthesis described herein provides several advantages over previous methods: (1) The starting compounds are all relatively inexpensive; (2) the yield of product is greater than 20% of the theoretical yield; and (3) the steps of synthesis are easy, inexpensive and amenable to large-scale production. All of these advantages allow for less expensive production of ethyleneimine dimer.
Other features and advantages of the invention will be apparent from the following detailed description and from the claims.
Detailed Description An example. of the synthesis is provided below. From the description provided herein, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Example: Synthesis of ethyleneimine dimer Step 1: Synthesis of N-(2-bromoeth,~l)-1,2-ethanediamine dihydrobromide from 2-(2-aminoethylamino)ethanol N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide is synthesized as follows. 100 mL of chilled (0.99 moles) of 2-(2-aminoethylamino)ethanol is placed in an ice bath for about 30-45 minutes. 1L (8.84 moles) of 48% (w/w) hydrobromic acid is added dropwise over 1.5 hours. This mixture is distilled in a vigreux distillation apparatus until the temperature distillate is 124 C
(three hours), refluxed for four hours, distilled to 124 C (1.5 hours), refluxed for four hours, distilled to 124 C (30 minutes), refluxed for four hours, distilled to 124 C (30 minutes), refluxed for four hours, and distilled to 124 C (10 minutes). The remainder of the HBr is removed when the mixture is cooled and concentrated on a rotary evaporator under vacuum at 6 mm pressure. The resulting residue is dissolved in boiling EtOH/H20 (1175mL/125mL) and allowed to crystallize at 4 C for about 12 hours. The crystals are collected by filtration, washed with cold ethanol, and then recrystallized from EtOH/H20 as described above. The crystals are collected by filtration, washed with cold EtOH, and dried in an oven under vacuum at 6mm pressure at -60 C for 12 hours. The yield is approximately 254.4g (78% of theoretical yield) of white solid with a melting point of 170-171 C. This white powder is N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide. Thin layer chromatography shows trace of a more-polar impurity.
A higher percent yield of N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide can be obtained by allowing the pot residue remaining after the final vigreux distillation to cool to 95 C, and then adding to this pot residue l OOmL of 100% ethanol. N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide will crystallize overnight. The solid is collected and washed several times with ice cold 100% ethanol. This yield is approximately 87% of theoretical yield.
The amount of HBr can be reduced to approximately 4 moles for every 1 mole of 2-(2-aminoethylamino)ethanol, thus reducing the cost of synthesis.
Step 2: Synthesis of ethyleneimine dimer from N-(2-bromoethyl)-1 2 ethanediamine dihydrobromide Ethyleneimine dimer is synthesized as follows. Sodium hydroxide (32.04g) is dissolved in 50mL deionized water and chilled in an ice bath to below 25 C. To this solution is added 65.78g (0.2 moles) of N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide and 250mL ethanol. The reaction mixture is refluxed for about one hour. The reaction mixture is cooled, then distilled in a vigreux distillation apparatus under reduced pressure to remove the bulk of the ethanol. The pot residue is loaded into a continuous extractor and extracted with ether for 42 hours. The ether extract is dried over sodium sulfate, filtered, and then distilled through a vigreux column first under argon and then under reduced pressure. Fractions with a high percentage of dimer (as determined by gas chromatography) are further distilled two or more times (the final distillation from sodium) to give 5.2g of a clear, colorless liquid, with a boiling point of 78-80 C at 138mm Hg. This liquid is 99.3% ethyleneimine dimer by gas chromatography, corresponding to a 30% yield (2.6% water by Karl Fischer water determination).
Ethyleneimine dimer can also be synthesized from N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide as follows. 1.152kg of sodium hydroxide (28.8 moles) is placed into a 12L three-neck round bottom flask. To this is added 5.85L of HPLC-grade methanol. The reaction mixture is cooled for about two hours to 8 C. 2.367kg (7.2 moles) of N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide is then added to the reaction mixture over 15 minutes. The temperature should be about 9 C at the end of the addition. The reaction mixture is refluxed for one hour, and then cooled to room temperature.
The solid is removed by filtration, and the methanol is distilled from the filtrate under argon atmosphere. The distillate should be about 5.52L. The pot residue is cooled to room temperature under argon and additional solid is removed by filtration. The filtrate is cooled in a 4 C refrigerator for four hours, and newly formed solid is removed by filtration. The filtrate is distilled through a vigreux column under vacuum (138mm Hg) and fractions are collected. Ethyleneimine content is determined using gas chromatography. Fractions with a high percentage of dimer (as determined by gas chromatography) are distilled to purity, as described above, resulting in 186g of a clear, colorless liquid with a boiling point of 78-80 C at 138 mm Hg. The yield is 30% of theoretical yield.
Background of the Invention The invention relates to methods for synthesizing compounds for the selective modification of nucleic acids in biological compositions.
The transmission of viral diseases (e.g., hepatitis A, B, and C, acquired immunodeficiency syndrome, and cytomegalovirus infections) by blood or blood products is a significant problem in medicine. Other biological compositions, such as mammalian and hybridoma cell lines, products of cell lines, milk, colostrum, and sperm, can also contain infectious viruses.
Screening donor biological compositions for viral markers can help reduce the transmission of viruses to recipients, but many screening methods are directed to only a few discrete viruses, and are therefore incomplete, and may also be less than 100% sensitive. It is therefore important to inactivate viruses contained in donor blood, blood products, or other biological compositions.
A number of agents that are capable of inactivating viruses in blood have been developed. For example, ethyleneimine monomer and ethyleneimine oligomers (including dimers, trimers, and tetramers) are very effective viral inactivating agents.
Summary of the Invention In general, the invention provides a method for synthesizing ethyleneimine dimer (1-aziridineethanamine) which includes reacting 2-(2-aminoethylamino)ethanol with an aqueous HX solution, where X is a halogen, to produce N-(2-haloethyl)-1,2-ethanediamine dihvdrohalide. reacting the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide with a base in a solvent to convert the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide into ethyleneimine dimer, and then purifying the dimer from the solvent (e.g., by continuous extraction).
In preferred embodiments, the halogen is bromine (most preferred), chlorine, fluorine, or iodine. In another preferred embodiment, the HX is diluted, such that the solution is 30-55% (w/w) HX. In yet another preferred embodiment, the solvent includes a C,_6alcohol (e.g., ethanol or methanol) or water.
In other preferred embodiments, the HX is added drop-wise to the 2-(2-aminoethylamino)ethanol, the temperature of the 2-(2-aminoethylamino) ethanol is less than 10 C during the addition of the HX, and the reaction of 2-(2-aminoethyl amino)ethanol with HX includes the step of refluxing. Preferably, the yield of the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide from this reaction is at least 50% of the theoretical yield.
More preferably, the yield is at least 75% of the theoretical yield.
In still other preferred embodiments, reacting the N-(2-haloethyl)-1,2-ethanediamine dihydrohalide to produce ethyleneimine dimer includes the steps of refluxing and distillation. Preferably, the yield of ethyleneimine dimer from this reaction is at least 20% of the theoretical yield. More preferably, the yield is at least 25% of the theoretical yield, and most preferably, the yield is at least 30% of the theoretical yield.
Preferably, the ethyleneimine dimer which results from the method of synthesis is at least 90% pure, more preferably at least 95% pure, and most preferably at least 98% pure.
The method of synthesis described herein provides several advantages over previous methods: (1) The starting compounds are all relatively inexpensive; (2) the yield of product is greater than 20% of the theoretical yield; and (3) the steps of synthesis are easy, inexpensive and amenable to large-scale production. All of these advantages allow for less expensive production of ethyleneimine dimer.
Other features and advantages of the invention will be apparent from the following detailed description and from the claims.
Detailed Description An example. of the synthesis is provided below. From the description provided herein, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Example: Synthesis of ethyleneimine dimer Step 1: Synthesis of N-(2-bromoeth,~l)-1,2-ethanediamine dihydrobromide from 2-(2-aminoethylamino)ethanol N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide is synthesized as follows. 100 mL of chilled (0.99 moles) of 2-(2-aminoethylamino)ethanol is placed in an ice bath for about 30-45 minutes. 1L (8.84 moles) of 48% (w/w) hydrobromic acid is added dropwise over 1.5 hours. This mixture is distilled in a vigreux distillation apparatus until the temperature distillate is 124 C
(three hours), refluxed for four hours, distilled to 124 C (1.5 hours), refluxed for four hours, distilled to 124 C (30 minutes), refluxed for four hours, distilled to 124 C (30 minutes), refluxed for four hours, and distilled to 124 C (10 minutes). The remainder of the HBr is removed when the mixture is cooled and concentrated on a rotary evaporator under vacuum at 6 mm pressure. The resulting residue is dissolved in boiling EtOH/H20 (1175mL/125mL) and allowed to crystallize at 4 C for about 12 hours. The crystals are collected by filtration, washed with cold ethanol, and then recrystallized from EtOH/H20 as described above. The crystals are collected by filtration, washed with cold EtOH, and dried in an oven under vacuum at 6mm pressure at -60 C for 12 hours. The yield is approximately 254.4g (78% of theoretical yield) of white solid with a melting point of 170-171 C. This white powder is N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide. Thin layer chromatography shows trace of a more-polar impurity.
A higher percent yield of N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide can be obtained by allowing the pot residue remaining after the final vigreux distillation to cool to 95 C, and then adding to this pot residue l OOmL of 100% ethanol. N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide will crystallize overnight. The solid is collected and washed several times with ice cold 100% ethanol. This yield is approximately 87% of theoretical yield.
The amount of HBr can be reduced to approximately 4 moles for every 1 mole of 2-(2-aminoethylamino)ethanol, thus reducing the cost of synthesis.
Step 2: Synthesis of ethyleneimine dimer from N-(2-bromoethyl)-1 2 ethanediamine dihydrobromide Ethyleneimine dimer is synthesized as follows. Sodium hydroxide (32.04g) is dissolved in 50mL deionized water and chilled in an ice bath to below 25 C. To this solution is added 65.78g (0.2 moles) of N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide and 250mL ethanol. The reaction mixture is refluxed for about one hour. The reaction mixture is cooled, then distilled in a vigreux distillation apparatus under reduced pressure to remove the bulk of the ethanol. The pot residue is loaded into a continuous extractor and extracted with ether for 42 hours. The ether extract is dried over sodium sulfate, filtered, and then distilled through a vigreux column first under argon and then under reduced pressure. Fractions with a high percentage of dimer (as determined by gas chromatography) are further distilled two or more times (the final distillation from sodium) to give 5.2g of a clear, colorless liquid, with a boiling point of 78-80 C at 138mm Hg. This liquid is 99.3% ethyleneimine dimer by gas chromatography, corresponding to a 30% yield (2.6% water by Karl Fischer water determination).
Ethyleneimine dimer can also be synthesized from N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide as follows. 1.152kg of sodium hydroxide (28.8 moles) is placed into a 12L three-neck round bottom flask. To this is added 5.85L of HPLC-grade methanol. The reaction mixture is cooled for about two hours to 8 C. 2.367kg (7.2 moles) of N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide is then added to the reaction mixture over 15 minutes. The temperature should be about 9 C at the end of the addition. The reaction mixture is refluxed for one hour, and then cooled to room temperature.
The solid is removed by filtration, and the methanol is distilled from the filtrate under argon atmosphere. The distillate should be about 5.52L. The pot residue is cooled to room temperature under argon and additional solid is removed by filtration. The filtrate is cooled in a 4 C refrigerator for four hours, and newly formed solid is removed by filtration. The filtrate is distilled through a vigreux column under vacuum (138mm Hg) and fractions are collected. Ethyleneimine content is determined using gas chromatography. Fractions with a high percentage of dimer (as determined by gas chromatography) are distilled to purity, as described above, resulting in 186g of a clear, colorless liquid with a boiling point of 78-80 C at 138 mm Hg. The yield is 30% of theoretical yield.
The purity of the synthesized ethyleneimine dimer is determined using standard methods of gas chromatography known to those skilled in the art. A suitable column is a Restek Rtx -5 15m x 0.53mm x 1.0 m analytical column, compatible with, for example, a Hewlett Packard Model 6890 Series with FID detection. Using the method of synthesis described herein, the ethyleneimine dimer is at least 98% pure. Thin layer chromatography shows piperazine as an impurity.
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of synthesizing ethyleneimine dimer, said method comprising the steps:
(a) reacting 2-(2-aminoethylamino)ethanol with an aqueous HX solution, where X is a halogen, to produce N-(2-haloethyl)-1,2-ethanediamine dihydrohalide;
(b) reacting said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide with a base in a solvent to convert said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide into ethyleneimine dimer; and (c) purifying said ethyleneimine dimer from said solvent;
wherein said ethyleneimine dimer is at least about 90% (w/w) pure after said purifying step.
(a) reacting 2-(2-aminoethylamino)ethanol with an aqueous HX solution, where X is a halogen, to produce N-(2-haloethyl)-1,2-ethanediamine dihydrohalide;
(b) reacting said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide with a base in a solvent to convert said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide into ethyleneimine dimer; and (c) purifying said ethyleneimine dimer from said solvent;
wherein said ethyleneimine dimer is at least about 90% (w/w) pure after said purifying step.
2. The method of claim 1, wherein X is Br or Cl.
3. The method of claim 2, wherein X is Br.
4. The method of claim 1, wherein said HX solution is 30-55% (w/w) HX.
5. The method of claim 1, wherein said solvent comprises water or a C1-6 alcohol.
6. The method of claim 1, wherein said HX solution is added to said 2-(2-aminoethylamino)ethanol such that the temperature of the reaction mixture is less than 10°C. during said addition.
7. The method of claim 1, wherein said HX is added drop-wise to said 2-(2-aminoethylamino)ethanol.
8. The method of claim 1, wherein said reacting 2-(2-aminoethyl amino)ethanol with HX comprises the step of refluxing.
9. The method of claim 1, wherein the yield of said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide from said 2-(2-aminoethylamino)ethanol is at least 50% of the theoretical yield.
10. The method of claim 1, wherein the yield of said N-(2-haloethyl) 1,2-ethanediamine dihydrohalide from said 2-(2-aminoethylamino)ethanol is at least 75% of the theoretical yield.
11. The method of claim 5, wherein said reacting said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide in said C1-6 alcohol to produce ethyleneimine dimer comprises the step of refluxing.
12. The method of claim 1, wherein said reacting said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide to produce ethyleneimine dimer comprises the step of distillation.
13. The method of claim 1, wherein said purifying comprises a continuous extraction.
14. The method of claim 1, wherein said purifying comprises a series of distillations and filtrations.
15. The method of claim 1, wherein said ethyleneimine dimer is at least 95%
(w/w) pure after said purifying step.
(w/w) pure after said purifying step.
16. The method of claim 1, wherein said ethyleneimine dimer is at least 98%
(w/w) pure after said purifying step.
(w/w) pure after said purifying step.
17. The method of claim 1, wherein the yield of said ethyleneimine dimer from said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide is at least 20% of the theoretical yield.
18. The method of claim 1, wherein the yield of said ethyleneimine dimer from said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide is at least 25% of the theoretical yield.
19. The method of claim 1, wherein the yield of said ethyleneimine dimer from said N-(2-haloethyl)-1,2-ethanediamine dihydrohalide is at least 30% of the theoretical yield.
20. A method of synthesizing ethyl ethyleneimine dimer, said method comprising the steps:
(a) reacting 2-(2-aminoethylamino)ethanol with HBr to produce N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide; and (b) reacting said N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide with a base in a solvent having a pH > 7.5 to convert said N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide into ethyleneimine dimer;
wherein said ethyleneimine dimer is at least about 90% (w/w) pure after said purifying step.
(a) reacting 2-(2-aminoethylamino)ethanol with HBr to produce N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide; and (b) reacting said N-(2-bromoethyl)- 1,2-ethanediamine dihydrobromide with a base in a solvent having a pH > 7.5 to convert said N-(2-bromoethyl)-1,2-ethanediamine dihydrobromide into ethyleneimine dimer;
wherein said ethyleneimine dimer is at least about 90% (w/w) pure after said purifying step.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11778999P | 1999-01-29 | 1999-01-29 | |
| US60/117,789 | 1999-01-29 | ||
| PCT/US2000/002184 WO2000044720A1 (en) | 1999-01-29 | 2000-01-28 | Synthesis of ethyleneimine dimer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2361565A1 CA2361565A1 (en) | 2000-08-03 |
| CA2361565C true CA2361565C (en) | 2008-11-18 |
Family
ID=22374836
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002361565A Expired - Fee Related CA2361565C (en) | 1999-01-29 | 2000-01-28 | Synthesis of ethyleneimine dimer |
Country Status (7)
| Country | Link |
|---|---|
| US (2) | US6215003B1 (en) |
| EP (1) | EP1147082A4 (en) |
| JP (1) | JP2002535389A (en) |
| AU (1) | AU2975100A (en) |
| CA (1) | CA2361565C (en) |
| HK (1) | HK1043114A1 (en) |
| WO (1) | WO2000044720A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040053208A1 (en) * | 1995-08-29 | 2004-03-18 | V. I. TECHNOLOGIES, Inc. | Methods to selectively inactivate parasites in biological compositions |
| EP1549761A4 (en) * | 2002-05-06 | 2006-02-15 | Vi Technologies Inc | Methods and compositions for the modification of nucleic acids |
| EP1945604A1 (en) * | 2005-11-03 | 2008-07-23 | Albermarle Corporation | Process for the preparation of (omega-aminoalkylamino)alkyl halides and conversion to amifostine |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3324130A (en) * | 1965-03-24 | 1967-06-06 | Dow Chemical Co | Manufacture of piperazine |
| US3487157A (en) | 1966-10-31 | 1969-12-30 | Allied Chem | Novel n-substituted aziridine compositions and method for combating microorganisms therewith |
| US3502654A (en) * | 1967-04-12 | 1970-03-24 | Dow Chemical Co | Process for preparing alkylenimine dimers |
| SU1177297A1 (en) * | 1983-02-28 | 1985-09-07 | Inst Chimii Bashkirskogo | Method of producing 1-(2-aminoethyl) ethyleneimine |
| SU1266847A1 (en) | 1983-07-08 | 1986-10-30 | Предприятие П/Я В-8469 | Method of producing 1-(2-aminoethyl)-ethyleneimine |
| SU1300021A1 (en) | 1985-02-05 | 1987-03-30 | Предприятие П/Я В-8469 | Unfritted glaze |
| SU1364620A1 (en) | 1986-04-29 | 1988-01-07 | Институт Химической Физики Ан Ссср | Method of obtaining 1-(2-aminoethyl)-aziridine |
| SU1696505A1 (en) | 1989-10-09 | 1991-12-07 | Институт химической физики им.Н.Н.Семенова | Method of 1-(2-aminoethyl)-aziridine preparation |
| US5231189A (en) * | 1990-06-21 | 1993-07-27 | Nippon Shokubai Co., Ltd. | Process for producing n-substituted aziridine compound |
-
2000
- 2000-01-28 AU AU29751/00A patent/AU2975100A/en not_active Abandoned
- 2000-01-28 EP EP00908404A patent/EP1147082A4/en not_active Withdrawn
- 2000-01-28 US US09/493,544 patent/US6215003B1/en not_active Expired - Fee Related
- 2000-01-28 JP JP2000595976A patent/JP2002535389A/en active Pending
- 2000-01-28 CA CA002361565A patent/CA2361565C/en not_active Expired - Fee Related
- 2000-01-28 WO PCT/US2000/002184 patent/WO2000044720A1/en not_active Application Discontinuation
-
2001
- 2001-03-26 US US09/817,817 patent/US6559321B2/en not_active Expired - Fee Related
-
2002
- 2002-04-18 HK HK02102945.0A patent/HK1043114A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000044720A1 (en) | 2000-08-03 |
| CA2361565A1 (en) | 2000-08-03 |
| EP1147082A4 (en) | 2002-05-08 |
| US20010014744A1 (en) | 2001-08-16 |
| AU2975100A (en) | 2000-08-18 |
| US6215003B1 (en) | 2001-04-10 |
| JP2002535389A (en) | 2002-10-22 |
| HK1043114A1 (en) | 2002-09-06 |
| EP1147082A1 (en) | 2001-10-24 |
| US6559321B2 (en) | 2003-05-06 |
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